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Novel therapeutics for brain cancer

Inactive Publication Date: 2015-09-17
RGT UNIV OF CALIFORNIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent describes a way to stop a protein called Olig2 from being active in a cell. This is done by using certain peptides, peptidomimes, or cyclic peptides that are provided here. The technical effect of this invention is that it allows for more precise targeting and inhibition of specific proteins, which can be useful in research and development of new treatments for diseases.

Problems solved by technology

Current brain tumor therapeutic agents, which are only able to extend median survival of patients to six months, cause significant systemic toxicity.
This toxicity results in serious long term morbidity of the few patients that survive, in terms of cognition, endocrine disorders, and motor effects.

Method used

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  • Novel therapeutics for brain cancer
  • Novel therapeutics for brain cancer
  • Novel therapeutics for brain cancer

Examples

Experimental program
Comparison scheme
Effect test

example 1

A. Example 1

[0397]In some embodiments, the compounds (e.g., compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), or (IX)) described herein interfere with Olig2 dimerization with itself and partner proteins by blocking binding hotspots within the dimerization region. The pharmacophore for this region is defined herein (FIG. 1). The pharmacophore shown in FIG. 1 was used in generating an in silico compound search of small molecules described herein (e.g., in Table 1 or 2). The inhibitors in Table 3 were screen in a cell-based glioblastoma assay. These molecules were used in the design of additional inhibitors (Tables 1 and 2).

[0398]Table 3 feft column in table is compound number, second column is chemical registry number, middle column shows the structure, and the last column indicates the IC50 in micromoles (μM) for human glioblastoma cells in culture.

example 2

B. Example 2

[0399]From the dimerization region of Olig2 specific peptide sequences have been identified, which are shown in Table 4. These sequences are important in generating peptide probes for testing dimerization inhibition and are the basis of making peptidomimetic molecules. The sequence of the OLIG2 molecule directly involved in dimerization has been identified:

RLKINSRERKRMHDLNIAMDGLREVMPYAHGPSVRKLSKIATLLLARNYILMLTNSL

[0400]Table 4 lists peptide sequences predicted to bind the brown and gray colored regions which are most important for dimerization. Some sequences overlap both the loop and the direct contact sites which may increase target affinity. Sequence number 12 is a probe for the loop region, as this may block dimerization. The peptide RNYILMLTN has been synthesized.

[0401]Applicants have performed homology modeling of E47 and OLIG2 based on the crystal structure of E47 and the amino acid sequence of both proteins, and have identified the dimerization region of OLIG2.

[04...

example 3

C. Example 3

[0406]Applicants have optimized the design of several novel druggable Olig2 inhibitors. These new compounds are shown in Table 1 and 2 below. Tables 1 and 2 show analogues of Olig2 inhibitors from a pharmacophore similarity search with improved druggability profiles.

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Abstract

Provided herein are novel compositions and methods to inhibit Olig2 activity. The Olig2 inhibitors and methods of using the same are useful, inter alia, for treating cancer. In particular the Olig2 inhibitors may be used to treat glioblastoma. Further, provided are peptide compositions capable of inhibiting Olig 2.

Description

CROSS-REFERENCES TO RELATED APPLICATIONS[0001]This application is a continuation of PCT Application No. PCT / US2013 / 045968, filed Jun. 14, 2013, entitled “NOVEL THERAPEUTICS FOR BRAIN CANCER” which claims priority to U.S. Provisional Patent Application No. 61 / 660,631, filed Jun. 15, 2012, entitled “NOVEL THERAPEUTICS FOR BRAIN CANCER” the disclosures of which are incorporated by reference herein in their entirety.STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT[0002]This invention was made with government support under grant numbers CA023100 and CA124804 awarded by the National Institutes of Health. The Government has certain rights in the invention.REFERENCE TO A SEQUENCE LISTING APPENDIX SUBMITTED AS AN ASCII TEXT FILE[0003]The Sequence Listing written in file 88654-924304_ST.TXT, created on Jan. 28, 2015, 16,535 bytes, machine format IBM-PC, MS-Windows operating system, is hereby incorporated by reference.BACKGROUND OF THE INVENTION[0004...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12C07D233/02C07D233/24C07D239/48C07D239/50C07D401/14C07D403/04C07D403/12C07D413/04C07D413/12C07D413/14C07D417/04C07D417/12C07D417/14C07D471/04C07D471/14C07D471/22A61K31/4545A61K31/506A61P25/00A61P25/28A61P35/00A61P35/02
Inventor KESARI, SANTOSHMAKALE, MILANWRASIDLO, WOLFMUKTHAVARAM, RAJESHTSIGELNY, IGOR FLINTKOUZNETSOVA, VALENTINA LEA
Owner RGT UNIV OF CALIFORNIA
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